Full text of DOI:10.1038/sj.bjp.0704585

British Journal of Pharmacology (2002) 135, 1540 ± 1546
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Inhibition of cyclo-oxygenase-2 exacerbates ischaemia-induced
acute myocardial dysfunction in the rabbit
1
2
Giuseppe Rossoni, Marcelo N. Muscara, Giuseppe Cirino & * John L. Wallace
3
,2
1
2
Department of Pharmacological Sciences, University of Milan, Milan, Italy; Department of Pharmacology and Therapeutics,
3
University of Calgary, Calgary, Alberta, Canada and Department of Experimental Pharmacology, University of Naples,
Naples, Italy
1 The e€ects of treatment with a number of cyclo-oxygenase inhibitors, (celecoxib, meloxicam,
DuP-697 and aspirin) on ischaemia-reperfusion-induced myocardial dysfunction were examined
using an in vitro perfused rabbit heart model.
2
Ischaemia resulted in myocardial dysfunction, as indicated by a signi®cant increase in left
ventricular end diastolic pressure and marked changes in coronary perfusion pressure and left
ventricular developed pressure. In the post-ischaemic state, coronary perfusion pressure increased
dramatically, left ventricular developed pressure recovered to a small degree and there were
signi®cant increases in creatinine kinase release (indicative of myocardial damage) and prostacyclin
release.
3
Pretreatment with aspirin, or with drugs that selectively inhibit cyclo-oxygenase-2 (celecoxib,
meloxicam and DuP-697), resulted in a concentration-dependent exacerbation of the myocardial
dysfunction and damage. Exacerbation of myocardial dysfunction and damage was evident with
1
0 mM concentrations of the cyclo-oxygenase-2 inhibitors, which inhibited prostacyclin release but
did not a€ect cyclo-oxygenase-1 activity (as measured by whole blood thromboxane synthesis).
NCX-4016, a nitric oxide-releasing aspirin derivative, signi®cantly reduced the myocardial
4
dysfunction and damage caused by ischaemia and reperfusion. Bene®cial e€ects were observed even
at a concentration (100 mM) that signi®cantly inhibited prostacyclin synthesis by the heart.
5
The results suggest that prostacyclin released by cardiac tissue in response to ischaemia and
reperfusion is derived, at least in part, from cyclo-oxygenase-2. Cyclo-oxygenase-2 plays an
important protective role in a setting of ischaemia-reperfusion of the heart.
British Journal of Pharmacology (2002) 135, 1540 ± 1546.
Keywords: Prostaglandin; cardiovascular; nitric oxide; reperfusion; anti-in¯ammatory
Abbreviations: ANOVA, analysis of variance; AUC, area-under-the-curve; CK, creatine kinase; COX, cyclo-oxygenase; CPP,
coronary perfusion pressure; ELISA, enzyme-linked immunosorbent assay; LVDP, left ventricular developed
pressure; LVEDP, left ventricular end-diastolic pressure; LVP, left ventricular pressure; NSAID, nonsteroidal
2
anti-in¯ammatory drug; PGI , prostacyclin
Introduction
Nonsteroidal anti-in¯ammatory drugs (NSAIDs) are among
the most commonly used drugs, primarily for their anti-
in¯ammatory and analgesic properties. In addition to their
signi®cant toxicity in the gastrointestinal tract, NSAIDs have
well documented deleterious e€ects on the kidney. There are
con¯icting reports regarding the e€ects of NSAIDs in various
models of acute myocardial ischaemia (Ogletree & Lefer,
aspirin, respectively, aggravated ischaemia-induced ventricu-
lar dysfunction in perfused rabbit hearts and this was
2
associated with inhibition of prostacyclin (PGI ) synthesis
in the cardiac tissues. In contrast, exposure of the hearts to a
nitric oxide-releasing derivative of aspirin, NCX-4016,
resulted in a signi®cant reduction of cardiac dysfunction.
The cardioprotective e€ects of NCX-4016 were concentra-
tion-dependent and most likely mediated via the nitric oxide
generated by this compound (Rossoni et al., 2000).
In recent years a new class of NSAIDs has been developed,
namely the selective cyclo-oxygenase (COX)-2 inhibitors.
These agents exhibit anti-in¯ammatory and analgesic proper-
ties with reduced toxicity in the gastrointestinal tract
(Bombardier et al., 2000). However, selective COX-2
inhibitors have recently been shown to markedly reduce
1
976; Jugdutt et al., 1979). For example, ibuprofen has been
reported to reduce infarct size in canine hearts (Kirlin et al.,
982), while indomethacin has been reported to induce
1
coronary vasoconstriction in patients with coronary artery
disease (Friedman et al., 1981). Moreover, aspirin, which
inhibits platelet aggregation, does not improve exercise
tolerance, change the pain threshold, or alter ischaemic
electrocardiographic abnormalities in patients with angina
pectoris (Frishman et al., 1976). Berti et al. (1988) and
Rossoni et al. (2000) have reported that indomethacin and
whole body PGI
2
synthesis in healthy human volunteers
(McAdam et al., 1999; Catella-Lawson et al., 1999), to
signi®cantly elevate systemic blood pressure in rats and to
elicit a signi®cant increase in leukocyte adherence to the
vascular endothelium (Muscara et al., 2000). Moreover, there
have been a number of recent clinical reports of selective
*
Author for correspondence at: Department of Pharmacology and
Therapeutics, University of Calgary, 3330 Hospital Drive NW,
Calgary, Alberta, T2N 4N1, Canada; E-mail: wallacej@ucalgary.ca

G. Rossoni et al
COX-2 and myocardial dysfunction
1541
COX-2 inhibitors increasing the incidence of myocardial
infarction relative to that seen with a conventional NSAID
(Bombardier et al., 2000; Mukherjee et al., 2001) or
promoting thrombosis (Cro€ord et al., 2000).
COX-2 has been shown to be up-regulated in the
myocardium of patients with congestive heart failure (Wong
et al., 1998) and in the stomach of rats during ischaemia
Grass stimulator (model S-88; Grass Instruments, Quincy,
MA, U.S.A.). Ischaemia was induced by reducing the ¯ow
71
rate from 20 to 1 ml min for 40 min (ischaemic period). A
71
normal ¯ow rate (20 ml min ) was then restored and the
perfusion was continued for another 20 min (reperfusion
period).
Each of the NSAIDs was tested at concentrations of 1, 10
and 100 mM (n=6 ± 10 per group). The test drugs included
three that exhibit selectivity for COX-2: celecoxib (Silverstein
et al., 2000), DuP-697 (Gans et al., 1990) and meloxicam
(Engelhardt et al., 1995); a non-selective COX inhibitor
(aspirin) and the nitric oxide-releasing aspirin derivative,
NCX 4016 (Wallace et al., 1999). One of the test drugs, or
vehicle, was perfused through the hearts for 20 min before
the start of the period of ischaemia.
(
COX-2 may occur as defensive response, aimed at
Maricic et al., 1999). This suggests that up-regulation of
a
increasing the generation of vasodilatory prostaglandins. In
the stomach, treatment of rats with a selective COX-2
inhibitor during a period of ischaemia resulted in a marked
exacerbation of tissue injury (Maricic et al., 1999). It is
possible that a similar phenomenon may occur in the context
of myocardial ischaemia-reperfusion. Thus, in the present
study, we have tested the hypothesis that selective COX-2
inhibitors will exacerbate the myocardial dysfunction that
occurs as a consequence of ischaemia-reperfusion in an in
vitro perfused rabbit heart model. We have compared the
e€ects of exposure of the heart, prior to the period of
ischaemia, to a number of drugs with varying degrees of
selectivity for COX-2. For comparison, we have also assessed
the e€ects of exposure of the heart to the nitric oxide-
releasing aspirin derivative, NCX-4016.
Prostacyclin release and creatine kinase activity
The release of the PGI into the perfusate was measured by
2
determining the concentrations of its stable hydration produc-
tion, 6-keto-prostaglandin F1a (6-keto-PGF1a), using an en-
zyme-linked immunosorbent assay (ELISA) (Berti et al., 1993).
The perfusates were collected for 5 min immediately before the
period of ischaemia and during the ®rst 10 min of reperfusion.
Creatine kinase (CK) activity was measured in samples (taken
during the ischaemia and reperfusion periods) using the
spectrophotometric method of Bergmeyer et al. (1970).
Methods
The experimental procedures were approved by the Animal
Care Committees of the University of Milan and the
University of Calgary and the studies were performed in
accordance with the principles set forth in the Italian and
Canadian guidelines for the care and use of laboratory
animals.
Whole blood thromboxane synthesis
The synthesis of thromboxane by whole blood was
determined using the method of Patrono et al. (1980). Blood
was drawn from the descending aorta of rabbits into a
syringe. The blood was transferred into glass tubes (1 ml per
tube) to which the test drugs were added to give ®nal
concentrations of 1, 10 or 100 mM. The tubes of blood were
allowed to stand at 378C for 45 min, after which they were
centrifuged (1000 g; 10 min). The serum was transferred to
Eppendorf tubes then frozen at 7208C. Thromboxane B2
concentrations in the serum samples were measured using a
speci®c enzyme-linked immunosorbent assay, according to
the manufacturer's instructions (Wallace et al., 1998).
Ischaemia-reperfusion in isolated rabbit heart
Male, New Zealand White rabbits (BMG-Allevamento,
Cividate al Piano, BG, Italy or Reimans Fur Ranches,
Calgary, AB, Canada) weighing 2.0 ± 2.2 kg were used for
these experiments. The hearts were excized and perfused
retrogradely at 378C through the aorta as previously
described by Berti et al. (1988) and Rossoni et al. (2000).
The perfusion medium (Krebs Henseleit) contained (in mM):
Data analysis
NaCl 118, KCl 2.8, KH
NaHCO 25 and glucose 5.5. After a period of equilibration
2 4 2 4
PO 1.2, CaCl 2.5, MgSO 1.2,
Multiple group comparisons were made using analysis of
variance (ANOVA) and the Dunnett's multiple comparison
test. Comparisons of only two groups were made using the
Student's t-test with the Bonferroni correction. An associated
probability (P value) of less than 5% was considered
signi®cant. In all tables and ®gures, results are expressed as
mean+s.e.mean. Area under the curve (AUC) was estimated
according to the trapezoid method (Microcal Software Inc.,
Northampton, MA, U.S.A.).
3
with a 5% CO
perfusate was 7.4. The rate of perfusion was maintained at
2 2
and 95% O gas mixture, the pH of the
71
2
0 ml min with a roller pump (Minipuls-3, Gilson, Villiers-
Le Bel, France). Coronary perfusion pressure (CPP) and left
ventricular pressure (LVP) were measured with two HP-
1280C pressure transducers (Hewlett-Packard, Waltham,
MA, U.S.A.) connected to a Hewlett-Packard dynograph
(
(
HP-7754A). LVP was recorded with a polyethylene catheter
with a small latex balloon on the top) inserted in the left
ventricular cavity. The balloon was ®lled slowly with saline
until left ventricular end-diastolic pressure (LVEDP) stabi-
lized in the range of 4 ± 6 mmHg. Left ventricular developed
pressure (LVDP: peak left ventricular systolic pressure minus
LVEDP) was also evaluated. The hearts were electrically
Materials
NCX-4016 was obtained from NicOx S.A. (Sophia Antipolis,
France), celecoxib from Monsanto (St. Louis, MO, U.S.A.),
DuP-697 from DuPont-Merck (Dover, DE, U.S.A.), aspirin
from Sigma Chemical Co. (St. Louis, MO, U.S.A.) and
meloxicam from Boehringer-Ingelheim (Danbury, CT,
71
paced at a frequency of 180 beats min with rectangular
impulses (1 ms duration, voltage 10% above threshold) by a
British Journal of Pharmacology vol 135 (6)

1542
G. Rossoni et al
COX-2 and myocardial dysfunction
U.S.A.). The ELISA kits for determination of 6-keto-PGF1a
and thromboxane B were obtained from Amersham Italia
Milan, Italy) and Medicorp (Montreal, Canada), respec-
tively. The kits for creatine kinase determination were
obtained from Boehringer-Mannheim (Milan, Italy). NCX-
Effects of COX-2 inhibitors
2
(
When the hearts were perfused with celecoxib, DuP-697 or
meloxicam for 20 min before the ischaemia period, a
worsening of the cardiac mechanics was observed. This
aggravation, which occurred in a concentration-dependent
manner, consisted not only of an increase in ventricular
contraction (LVEDP; Figure 1), but also in the strength of
contractility (LVDP) during reperfusion (Figure 2). The
exacerbation of the ischaemic damage was also evident from
the concentration-dependent augmentation of CPP and an
increase in CK activity during reperfusion (Figures 3 and 4).
Each of the COX-2 inhibitors dose-dependently inhibited the
release of 6-keto-PGF1a into the perfusate (Figure 5). Whole
blood thromboxane synthesis was measured as an index of
COX-1 activity (Wallace et al., 2000). Each of the selective
COX-2 inhibitors spared thromboxane synthesis at the lower
two concentrations, but inhibited thromboxane synthesis (by
*50%) at the highest concentration tested (Figure 5).
4
016 and aspirin were initially dissolved in dimethylsulph-
oxide, then diluted in Krebs Henseleit solution (®nal
concentration of dimethylsulphoxide was 51%). All other
drugs were dissolved directly in the Krebs Henseleit solution.
Results
Effects of ischaemia-reperfusion
The reduction of the perfusion ¯ow-rate of electrically paced
isovolumic left heart preparations for 40 min resulted in a
progressive increase in left ventricular end diastolic pressure
(Figure 1). During reperfusion, left ventricular developed
pressure was signi®cantly reduced (Figure 2) and coronary
perfusion pressure (CPP) increased consistently above base-
line (Figure 3). Moreover, there was a marked increase in
creatine kinase (CK) activity in the cardiac perfusates during
the reperfusion period, reaching a maximum at 45 ± 50 min of
the reperfusion (Figure 4). In the pre-ischaemic period, 6-keto
PGF1a was detectable in the perfusates (mean release of
Effects of aspirin and NCX-4016
Aspirin produced e€ects similar to those of the selective
COX-2 inhibitors; that is, an augmentation of the myocardial
dysfunction induced by ischaemia and reperfusion (Figures
1 ± 4). Aspirin also caused signi®cant inhibition of the
71
2
period, the release of 6-keto PGF1a increased approximately
.7+0.2 ng min ). During the ®rst 10 min of the reperfusion
71
3
fold (mean release of 8.7+0.8 ng min ).
Figure 2 E€ect of cyclo-oxygenase inhibitors on left ventricular
developed pressure (LVDP) in paced isovolumic left heart prepara-
Figure 1 E€ect of cyclo-oxygenase inhibitors on left ventricular
end-diastolic pressure (LVEDP) in paced isovolumic left heart
preparations subjected to low-¯ow ischaemia (1 ml min7 for
71
tions subjected to low-¯ow ischaemia (1 ml min
for 40 min) and
1
71
reperfusion (20 ml min for 20 min). The compounds were infused
for 20 min before reduction of ¯ow The upper panel shows the e€ect
of the 100 mM concentration of each drug. The lower panel shows the
area-under-the-curve (AUC) during the reperfusion period for all
three concentrations of each test drug. *P50.05, **P50.01,
***P50.001 versus the vehicle-treated group. Each point/bar
represents the mean (+s.e.mean in the lower panel) of 6 ± 10
experiments.
71
4
0 min) and reperfusion (20 ml min for 20 min). The compounds
were infused for 20 min before reduction of ¯ow. The upper panel
shows the e€ect of the 100 mM concentration of each drug. The lower
panel shows the area-under-the-curve (AUC) for all three concentra-
tions of each test drug. *P50.05, **P50.01, ***P50.001 versus the
vehicle-treated group. Each point/bar represents the mean+s.e.mean
of 6 ± 10 experiments.
British Journal of Pharmacology vol 135 (6)

G. Rossoni et al
COX-2 and myocardial dysfunction
1543
Figure 3 E€ect of cyclo-oxygenase inhibitors on coronary perfusion
pressure (CPP) in paced isovolumic heart preparations subjected to
7
1
low-¯ow ischaemia (1 ml min
for 40 min) and reperfusion
for 20 min). The compounds were infused for 20 min
before the reduction of ¯ow. The upper panel shows the e€ect of the
00 mM concentration of each drug. The lower panel shows the area-
Figure 4 E€ect of cyclo-oxygenase inhibitors on creatine kinase
CK) activity in perfusates of rabbit heart preparations subjected to
71
(
20 ml min
(
71
low-¯ow ischaemia (1 ml min
for 40 min) and reperfusion
20 ml min for 20 min). The compounds were infused for 20 min
before reduction of ¯ow. The upper panel shows the e€ect of the
00 mM concentration of each drug. The lower panel shows the area-
under-the-curve (AUC) for all three concentrations of each test drug.
P50.05, **P50.01, ***P50.001 versus the vehicle-treated group.
1
71
(
under-the-curve (AUC) during the reperfusion period for all three
concentrations of each test drug. *P50.05, **P50.01, ***P50.001
versus the vehicle-treated group. Each point/bar represents the mean
1
(
+s.e.mean in the lower panel) of 6 ± 10 experiments.
*
Each point/bar represents the mean (+s.e.mean in the lower panel)
of 6 ± 10 experiments.
generation of 6-keto PGF1a, of a similar magnitude to that
seen with the COX-2 inhibitors. However, the inhibitory
e€ects of aspirin on thromboxane synthesis were observed at
increases during myocardial ischaemia (Berti et al., 1993),
and this was con®rmed in the present study. This increase in
prostacyclin synthesis reduces the vasospasm that occurs as a
result of ischaemia, in part by reducing the vasoconstrictive
e€ects of endothelin-1 (Berti et al., 1993), which has been
shown to be released into plasma during acute myocardial
ischaemia (Miyauchi et al., 1989).
The results of this study also suggest that COX-2 is the
source of a signi®cant proportion of the prostacyclin that was
released in response to ischaemia and reperfusion. COX-2 has
been shown to be expressed in the vascular endothelium
a
lower concentration (10 mM) than that required for
inhibition by the selective COX-2 inhibitors (Figure 5).
As previously observed (Rossoni et al., 2000), perfusion of
the hearts with NCX-4016 resulted in a dose-dependent
protection against ischaemia-reperfusion-associated cardiac
dysfunction (Figures 1 ± 4). This bene®cial e€ect was obtained
even with the highest concentration of NCX-4016, which
signi®cantly inhibited 6-keto-PGF1a generation (Figure 5). At
the highest concentration tested, NCX-4016 also signi®cantly
inhibited thromboxane synthesis (Figure 5).
(
Habib et al., 1993; Busija et al., 1996; Schmedtje et al., 1997;
Caughey et al., 2001) and in vascular smooth muscle (Vinals
et al., 1997). McAdam et al. (1999) demonstrated that in
healthy, young volunteers, selective suppression of COX-2
resulted in profound inhibition of total body excretion of
Discussion
This study demonstrates that COX inhibitors, such as aspirin,
celecoxib, meloxicam and DuP-697, aggravate the ischaemic
damage and dysfunction in electrically paced, left heart
preparations of the rabbit. These compounds aggravate the
decreased ventricular contractility during perfusion ¯ow
restriction and markedly increase the post-ischaemic ventri-
cular dysfunction. A common feature of these drugs, at the
concentrations that caused signi®cant exacerbation of
myocardial dysfunction and damage, is the signi®cant
suppression of prostacyclin generation by the heart tissue.
Previous studies have documented that prostacyclin synthesis
È
prostacyclin metabolites. Recently Schror et al. (1998)
demonstrated that subjecting perfused rabbit hearts to
ischaemia resulted in induction of COX-2 and a parallel
enhancement of prostacyclin generation. Schmedtje et al.
(1997) demonstrated that exposure of cultured human
endothelial cells to hypoxia resulted in rapid up-regulation
of COX-2, while Hennan et al. (2001) reported that COX-2-
derived prostacyclin played a key role in the maintenance of
blood ¯ow in a dog thrombosis model. These ®ndings are
consistent with our own observations that prostacyclin
British Journal of Pharmacology vol 135 (6)

1544
G. Rossoni et al
COX-2 and myocardial dysfunction
al., 2000) and mouse (Guo et al., 2000). However, COX-2
does not appear to play a role in the preconditioning induced
in rabbit by adenosine A1 or A3 agonists (Kodani et al.,
2
001).
It is important to bear in mind that the present study
involved the acute administration of selective COX-2
inhibitors. In a clinical setting, these agents are generally
used on a chronic basis. Whether or not chronic adminis-
tration of selective COX-2 inhibitors would similarly a€ect
susceptibility to myocardial dysfunction is not clear. It is
noteworthy, however, that a role of COX-2 in preservation
of myocardial function in a clinical setting has recently been
suggested. Chronic use of selective COX-2 inhibitors has
been suggested to increase the risk of serious cardiovascular
events, including myocardial infarction (Bombardier et al.,
2
000; Mukherjee et al., 2001). In one study, which excluded
patients at risk of acute myocardial infarction, use of the
selective COX-2 inhibitor rofecoxib was found to be
associated with *5-times as many myocardial infarctions
as observed in a group of similar patients taking naproxen,
a conventional NSAID (Bombardier et al., 2000). It has
been suggested that naproxen exerted a bene®cial e€ect, due
to inhibition of platelet aggregation, but there is little direct
evidence to support this hypothesis (Mukherjee et al., 2001).
Figure 5 Upper panel: e€ect of cyclo-oxygenase inhibitors on
release of 6-keto PGF1a in perfusates of rabbit heart preparations
71
subjected to low-¯ow ischaemia (1 ml min
reperfusion (20 ml min
for 40 min) and
for 20 min). The data shown are from
71
samples collected during the ®rst 10 min of the reperfusion period.
Lower panel: e€ects of cyclo-oxygenase inhibitors on whole blood
thromboxane synthesis in vitro. *P50.05, **P50.01, ***P50.001
versus the vehicle-treated group. The results are expressed as a
percentage of the levels of release of these prostanoids in the vehicle-
treated group. Each bar represents the mean+s.e.mean of 5 ± 10
experiments.
A
recent meta-analysis of trials with selective COX-2
inhibitors further suggested an association between use of
selective COX-2 inhibitors and myocardial infarction
(
Mukherjee et al., 2001).
As has been reported previously, NCX-4016 signi®cantly
reduced the myocardial dysfunction and damage caused by
ischaemia-reperfusion. This was in sharp contrast to the
other NSAIDs, despite the fact that NCX-4016 produced
signi®cant suppression of prostacyclin at the highest
concentration tested (comparable to the level of inhibition
observed with the highest concentratons of celecoxib and
DuP-697). Rossoni et al. (2001) have suggested that these
bene®cial e€ects of NCX-4016 are attributable to the
release of nitric oxide from this compound, and the
subsequent bene®cial e€ect that mediator would exert in
terms of preventing vasoconstriction of myocardial blood
vessels. They also reported that in perfused rabbit hearts,
synthesis increased signi®cantly following ischaemia, and that
three NSAIDs with selectivity for COX-2 each caused an
augmentation of myocardial dysfunction and damage at
concentrations at which they did not signi®cantly inhibit
COX-1 (as measured by the whole blood thromboxane
synthesis assay). It is noteworthy that there appeared to be
a parallel relationship between the ability of the COX-2
inhibitors to suppress prostacyclin synthesis and the degree of
augmentation of myocardial dysfunction and damage. This
was also true in the case of aspirin, which suppressed COX-1
G
(
thromboxane synthesis) in parallel with the suppression of
the blockade of nitric oxide synthase with N -mono-
prostacyclin synthesis. Of course, it is important to bear in
mind that the present study involved the acute administration
of selective COX-2 inhibitors. In a clinical setting, these
agents are generally used on a chronic basis. Whether or not
chronic administration of selective COX-2 inhibitors would
similarly a€ect susceptibility to myocardial dysfunction is not
clear.
methyl-L-arginine worsened the ischaemia-reperfusion da-
mage, an event prevented by prior treatment with NCX-
4016 but not by aspirin. Inhibition of nitric oxide
synthesis caused an even greater release of prostacyclin
from the perfused myocardial tissue (Berti et al., 1993),
further suggesting that the release of prostacyclin occurs as
a
consequence of the reduced ¯ow, as has been
COX-2-derived prostaglandins, particularly prostacyclin,
appear to play an important protective role during ischaemia-
reperfusion or other types of tissue stress. These ®ndings are
consistent with a number of recent studies. For example,
COX-2 was shown to be induced in the stomach by
ischaemia, and treatment with a COX-2 inhibitor resulted
in a marked exacerbation of damage (Maricic et al., 1999).
Dowd et al. (2001) reported that doxorubicin administration
to rats resulted in induction of COX-2, elevated prostacyclin
synthesis and cardiac injury. Administration of a selective
COX-2 inhibitor resulted in a signi®cant exacerbation of
cardiac injury. COX-2 also appears to play a role in
ischaemic preconditioning, in both the rabbit (Shinmura et
demonstrated previously (Rubanyi et al., 1986). More
recently, it has been reported that NCX-4016, but not
aspirin, dose-dependently reduced infarct size due to
myocardial ischaemia and reperfusion in anaesthetized rats
(Rossoni et al., 2001). These authors claimed that the
bene®cial e€ects of NCX-4016 appeared to be due
primarily to the nitric oxide release from this compound,
which could modulate a number of cellular events leading
to in¯ammation, coronary microcirculation obstruction,
arrhythmias and myocardial tissue necrosis.
Taken together, these ®ndings suggest that NSAIDs that
selectively inhibit COX-2 display negative e€ects in experi-
mental myocardial ischaemia-reperfusion similar to those
British Journal of Pharmacology vol 135 (6)

G. Rossoni et al
COX-2 and myocardial dysfunction
1545
Dr. Wallace is an Alberta Heritage Foundation for Medical
Research Senior Scientist. This work was supported by a grant
from the Heart and Stroke Foundation of Canada.
observed with conventional NSAIDs, such as aspirin. COX-
2-derived prostaglandins appear to perform an important
protective role in the heart during ischaemia-reperfusion.
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(Received October 1, 2001
Revised November 8, 2001
Accepted November 12, 2001)
British Journal of Pharmacology vol 135 (6)